Truncation of the human homologue of the Drosophila trithorax protein, HRX, by chromosomal translocations to form HRX fusion proteins is one of the most common genetic alterations in human acute leukemia. The aim of this proposal is to understand how truncated forms of HRX proteins, as nucleosome bound phosphatases, differ from wild-type protein and lead to leukemia. The objectives in Part I include a series of co-immunoprecipitation and in vitro reconstitution experiments aimed at substantiating the applicant's hypothesis that N-terminal and C-terminal HRX sequences cooperate to bind and regulate an okadaic acid-sensitive phosphatase. Part II is a set of experiments aimed at characterizing the DNA and nucleosome binding properties of truncated leukemic versions of HRX compared to wild-type protein. Part III includes functional assays to show that HRX and SET, akin to their related nucleosome binding factors, HMG-I(Y) and NAP-1 respectively, are active as chromatin remodeling factors in a series of nucleosome assembly/disassembly experiments. Finally, Part IV is a protein affinity purification scheme to identify a novel okadaic acid-insensitive phosphatase "I-PPase": a second phosphatase that the investigators have found co-immunoprecipitates with HRX.